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Conformational Transitions of Amyloid-β: A Langevin and Generalized Langevin Dynamics Simulation Study.

ABSTRACT: The dynamics of conformational transitions of the disordered protein, amyloid-β, is studied via Langevin and generalized Langevin dynamics simulations. The transmission coefficient for the unfold-misfold transition of amyloid-β is calculated from multiple independent trajectories that originate at the transition state with different initial velocities and are directly correlated to Kramers and Grote-Hynes theories. For lower values of the frictional coefficient, a well-defined rate constant is obtained, whereas, for higher values, the transmission coefficient decays with time, indicating a breakdown of the Kramers and Grote-Hynes theories and the emergence of a dynamic disorder, which demonstrates the presence of multiple local minima in the misfolding potential energy surface. The calculated free energy profile describes a two-state transition of amyloid-β in the energy landscape. The transition path time distribution computed from these simulations is compared with the related experimental and theoretical results for the unfold-misfold transition of amyloid-β. The high free energy barrier for this transition confirms the misfolding of amyloid-β. These findings offer an insight into the dynamics of the unfold-misfold transition of this protein.

SUBMITTER: Singh V

PROVIDER: S-EPMC8173568 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Extra unmatched nucleotides (single base bulges) are common structural motifs in folded RNA molecules and can participate in RNA-ligand binding and RNA tertiary structure formation. Often these processes are associated with conformational transitions in the bulge region such as flipping out of the bulge base from an intrahelical stacked toward a looped out state. Knowledge of the flexibility of bulge structures and energetics of conformational transitions is an important prerequisite to better understand the function of this RNA motif. Molecular dynamics simulations were performed on single uridine and adenosine bulge nucleotides at the center of eight basepair RNA molecules and indicated larger flexibility of the bulge bases compared to basepaired regions. The umbrella sampling method was applied to study the bulge base looping out process and accompanying conformational and free energy changes. Looping out toward the major groove resulted in partial disruption of adjacent basepairs and was found to be less favorable compared to looping out toward the minor groove. For both uridine and adenosine bulges, a positive free energy change for full looping out was obtained which was approximately 1.5 kcal mol-1 higher in the case of the adenosine compared to the uridine bulge system. The simulations also indicated stable partially looped out states with the bulge bases located in the RNA minor groove and forming base triples with 5'-neighboring basepairs. In the case of the uridine bulge this state was more stable than the intrahelical stacked bulge structure. Induced looping out toward the minor groove involved crossing of an energy barrier of approximately 3.5 kcal mol-1 before reaching the base triple state. A continuum solvent analysis of intermediate bulge states indicated that electrostatic interactions stabilize looped out and base triple states, whereas van der Waals interactions and nonpolar contributions favor the stacked bulge conformation.

Dataset Information

Conformational Transitions of Amyloid-β: A Langevin and Generalized Langevin Dynamics Simulation Study.

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